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REPRIEVE trial likely to clarify value of statins in HIV population
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As the HIV population ages, the rise in cardiovascular disease requires the thorough evaluation of optimal treatment strategies. The REPRIEVE trial will test whether daily statin therapy can prevent heart disease in HIV patients for whom statins are not already recommended. However, given the success of statin therapy in adults without HIV, Infectious Disease News asked several experts whether the trial is even necessary.
E. Turner Overton, MD
Associate professor
Division of infectious diseases
University of Alabama at Birmingham School of Medicine
It is currently estimated that HIV infection is associated with a similar increase in the risk for CVD as other accepted risk factors, such as hypertension or diabetes. While some of this excess risk can be explained by increased prevalence of certain traditional atherosclerotic cardiovascular disease risk factors among persons living with HIV infection, including tobacco use, dyslipidemia and abdominal fat accumulation, much of the data from research suggest the persistent inflammatory milieu associated with chronic viral infections like HIV, even in the setting of suppressive ART, is driving vascular inflammation and the process of atherosclerosis. In fact, the literature supports the notion that the process of atherosclerosis is inflammatory in nature, and diseases that are noted to increase systemic inflammation, including rheumatoid arthritis, inflammatory bowel diseases, diabetes and HIV, to name but a few, are associated with an accelerated progression of atherosclerosis.
HIV infection is associated with a 1.5- to twofold increase in atherosclerotic cardiovascular disease (ASCVD), but what approach should be taken to prevent the progression to clinical events such as myocardial infarctions (MI) and stroke? First and foremost is the suppression of HIV viremia. We have learned from many studies, including the Strategies for Management of Antiretroviral Therapy (SMART) study, as well as the CDC-funded Study to Understand the Natural History of HIV Infection (SUN), that uncontrolled viremia is associated with ASCVD events and more rapidly progressive atherosclerosis. But once we have control of the virus, what approach should providers undertake beyond risk-reduction strategies including management of key comorbidities like diabetes and hypertension, tobacco cessation, dietary counseling, and encouragement of exercise and good sleep hygiene?
The American Heart Association, in conjunction with the American College of Cardiology, recently published new guidelines that recommend the prescription of statins for a large proportion of the adult population based on underlying risk for CVD. However, these guidelines remain mute on whether persons living with HIV should be assessed differently from the general population.
The REPRIEVE trial is an NIH-funded randomized controlled trial of 6,500 persons living with HIV with a low 10-year risk for ASCVD based on the AHA/ACC risk calculator. These study participants will be randomly assigned to placebo or Livalo (pitavastatin, Kowa Pharmaceuticals), a relatively new statin with few drug-drug interactions and an excellent safety profile. The study will assess whether statin therapy can prevent ASCVD events and provide a comprehensive evaluation of the mechanisms driving excess ASCVD in persons living with HIV infection.
Some observers have suggested that the trial is not necessary because statins have been demonstrated to prevent ASCVD in HIV-negative populations, and we can simply extrapolate data from these studies and apply the findings to HIV-infected populations. Unfortunately, this approach is shortsighted for several reasons. First, the process of atherosclerosis appears accelerated with HIV infection, and we do not know to what degree statins will lead to regression or slowing of the process of atherosclerosis in this disease state. Additionally, we already know that existing data are not completely applicable to HIV infection because the risk algorithms used in the general population consistently underestimate the risk for ASCVD among persons living with HIV infection. Thirdly, the mechanisms through which statins prevent ASCVD may be very different in diseases that are characterized by excess chronic inflammation. Statins work by reducing low-density lipoprotein (LDL) cholesterol but also have pleiotropic anti-inflammatory effects that may be more profound in conditions like HIV infection.
Finally, there is growing literature suggesting statins may have important salutatory effects outside of atherosclerosis that may have important implications in the setting of HIV infection. Progressive liver disease and chronic kidney disease are two comorbidities that are more prevalent among HIV-infected populations than in the general adult population. There are data that support a further assessment of the role of statins to prevent progressive liver and kidney end-organ disease. Frailty, a geriatric syndrome that is associated with excess mortality in the elderly, has been reported to present at an earlier age among persons living with HIV infection.
Data suggest sarcopenia and decreased muscle function, key features of frailty, may be delayed or prevented by statin therapy. Without the REPRIEVE trial, these type of assessments will not be pursued in an adequately powered, rigorously performed study.
We do not know if statins will prevent ASCVD in the setting of lower risk HIV-infected populations. We do not know the mechanisms through which these agents will have their effects; is it mediated through effects on cholesterol or alterations in inflammation or other immune pathways? We do not know if statins will have important beneficial effects on other organ systems that are affected by HIV infection, such as muscle, kidney and liver. We need well-powered studies to address these issues to arm providers with robust data that will accurately inform their clinical decisions in the long-term management of our patients. In summary, we need the REPRIEVE trial to answer numerous questions within the field of HIV disease, inform how we manage our patients’ risk for ASCVD, and provide a greater understanding of how HIV infection drives the process of atherosclerosis and other aging-related comorbidities.
Vincent C. Marconi, MD
Associate professor
Division of infectious diseases
Emory University School of Medicine
The latest published guidelines from the American College of Cardiology/American Heart Association in 2013 recommend the use of statins for the treatment and prevention of ASCVD in adults. Although individuals living with HIV are not excluded from these recommendations, HIV was not identified as an independent risk factor for ASCVD similar to diabetes or smoking.
The primary mechanism of action for these agents is to reduce low density lipoproteins (LDL) —a known risk factor for ASCVD. Statins also lower systemic immune activation and chronic inflammation. Since the pathogenesis of noncalcified plaque rupture is affected by inflammation, this provides a secondary beneficial effect of statins. There is now overwhelming evidence that many individuals receiving ART continue to experience ongoing immune activation and chronic inflammation, thereby increasing the risk for ASCVD. Although there has been compelling evidence to suggest HIV is independently associated with disease, this evidence has not been strong enough to change the existing guidelines. Therefore, the National Heart, Lung, and Blood Institute in cooperation with the NIAID and the AIDS Clinical Trials Group, have launched a randomized controlled trial to address this very question.
The REPRIEVE (A5332) trial has been designed to determine the efficacy of pitavastatin as a primary prevention strategy for CV events targeting individuals living with HIV and receiving ART who do not meet the 2013 ACC/AHA guideline thresholds for initiating a statin. In addition to ASCVD, ongoing immune activation and chronic inflammation has been associated with other serious nonAIDS (SNA) clinical events such as malignancies, kidney or liver failure, and diabetes. It is conceivable that statins, which have demonstrated anti-inflammatory effects, could also have an impact on these outcomes. Therefore, the REPRIEVE study has important secondary endpoints to determine the efficacy of statin use in order to reduce the incidence of AIDS and other SNA clinical events for this same population.
For this study, 6,500 men and women living with HIV-1 aged 40 to 75 years receiving any ART regimen for at least 6 months prior to study entry and having a CD4+ T-cell count greater than 100 cells/mm3 as well as a low risk for ASCVD will randomly receive pitavastatin at a daily dose of 4 mg or a daily placebo. A low risk for ASCVD has been defined as no known clinical ASCVD, LDL less than 190 mg/dL and a 10-year ASCVD risk score estimated by Pooled Cohort Equations as less than 7.5%.
Participants will be followed for 72 months to observe clinical events in both arms throughout the trial period. A data and safety monitoring committee will periodically assess critical endpoints to determine whether the trial should be halted prematurely due to an imbalance in endpoints between arms. It is anticipated that these very important questions will be resolved by the end of the study. The world of HIV medicine eagerly awaits the results.
Todd Brown, MD, PhD
Associate professor of medicine and epidemiology
Division of endocrinology, diabetes and metabolism
Johns Hopkins University School of Medicine
We know from multiple studies outside of HIV-specific populations that statins are very effective at reducing the risk for CVD events — both for primary prevention and for secondary prevention. For this reason, statins are a mainstay of treatment. The same is true presumably for HIV-infected patients. Unless there is a contraindication, statins should be given to prevent cardiovascular events in HIV-infected persons who have had a previous CVD event (secondary prevention) and in those who have not had a CVD event, but who are at increased CVD risk based on their CVD risk factors.
The special concern in HIV-infected populations is threefold. First, there is an increased burden of some CVD risk factors in HIV-infected populations, such as hyperlipidemia, smoking and perhaps diabetes. Second, some ART may contribute independently of CVD risk. Third, there are additional factors related to chronic HIV infection that may contribute to cardiovascular disease that go beyond the risk conferred by traditional CVD risk factors. Chief among these is chronic inflammation and immune activation. Even with effective ART, chronic HIV infection is associated with heightened systemic inflammation and monocyte activation that has been associated with subclinical cardiovascular disease and CVD events. Perhaps for these reasons, CVD risk equations that were created in the general population, like the Framingham Risk Score or the AHA/ACC Pooled-Cohort Risk Equation, tend to underestimate the true risk for cardiovascular events in HIV-infected patients.
This leads to an important clinical question for primary prevention of CVD in HIV-infected patients: Where should the clinician draw the line regarding who to treat with a statin? Do we use the risk prediction equations that were generated in the general population, do we use a different equation specific to the HIV-infected population, or do we use the general population risk equations but treat at a lower risk? Another interesting question is whether, by giving statins to HIV patients, we can also decrease the incidence of other comorbidities, besides cardiovascular disease, that might be related to increased systemic inflammation.
That is where REPRIEVE comes in: taking a population of people who, under current guidelines would not be treated with a statin, and giving them a statin to see if the risk for CVD events and other comorbidities can be reduced. Investigators have tried to use observational data to get a sense of whether or not the incidence of CVD or these other comorbidities is different between statin users and nonusers, but these studies do not necessarily paint an accurate picture. The problem with using observational data to answer this question is that people go on statins for various reasons, which may cloud the relationship between statin use and the clinical outcome.
This is where a randomized, placebo-controlled trial like REPRIEVE really shows its value. By randomizing the allocation of the treatment and comparing the treatment to placebo, the investigators can truly determine the potential benefits of statins in this population. The results are sure to have a profound impact on how aggressive we are with statin treatment in HIV-infected populations.
Disclosure: Brown is a site investigator for REPRIEVE at Johns Hopkins University School of Medicine. Marconi is a site principal investigator of the ASPIRE study and, therefore, a subcontract awardee of a grant from ViiV Healthcare through Northwestern University. Overton is an investigator on the REPRIEVE trial. He reports no relevant financial disclosures.